UNC GI Cancer SPORE's unique goals emphasize multidisciplinary translational research that spans and links the population, clinical, and basic sciences. To decrease the burden of colorectal cancer on the patient population at large we will: (1) determine the clinical importance of new and existing targets on the colorectal cancer population (2) define the relationship of these molecular abnormalities to racial disparities (3) evaluate how best to manipulate these molecular targets for therapy, and (4) verify the target manipulation and effect in a group of colorectal cancer patients. To decrease colorectal cancer mortality a better understanding of the relationship of laboratory discoveries in signaling, oncogenesis and other molecular changes to the clinical setting is needed. We have developed projects that will allow us to accomplish these goals through the strong multi-disciplinary collaboration that already exists between clinical, laboratory and population-based scientists in the UNC Lineberger Comprehensive Cancer Center. The UNC GI Cancer SPORE's five projects and their translational objectives are: Project 1: Prognostic and Predictive Factors in Outcomes of Patients with Colorectal Cancer: A Population-Based Study. Determine which patient, treatment and molecular characteristics of colon cancer patients and their tumors will be predictive of prognosis, response to therapy and survival. Project 2: Molecular Changes in the NF-KappaB Pathway in Response to Chemoradiation Therapy in Rectal Cancer. Define in a clinical trial the NF-KappaB-related molecular responses of tumors and normal tissue during treatment compared to pre-treatment, the correlation of these responses with clinical outcome and the ability of proteasome inhibitors to modify this response to therapy. Using a variety of experimental models, determine if more specific approaches to NFkappaB inhibition will improve current regimens of colorectal cancer therapy. Project 3: Investigation of ERBB signaling in Colorectal Cancers during Liver Metastasis. To characterize, using patients with liver metastasis of colorectal cancer as a model, ERBB receptor activation, downstream signaling patterns and alterations in mRNA expression profiles of patients treated with a small molecule, dual kinase inhibitor in order to identify markers of response to ERBB directed therapy, to define reasons for treatment failure, and to correlate patient responses with the mouse model results. Project 4: Targeting the RAS>ERK Pathway for Colorectal Cancer Treatment. Determine whether a prospective group of patients with colorectal carcinomas that harbor mutated Ras show gene expression profiles that will predict their sensitivity to anti-Ras and anti-Raf or anti-MEK therapeutic strategies and to define the mechanisms for response or resistance. Project 5: Determination of the Role of Fucosyltransferases in Colorectal Cancer Initiation and Progression. To identify mutations and differential expression of human fucosyltransferases associated with the development of colorectal carcinoma, determine their potential interactions with NSAID use, apoptosis, diet and other genotypes, using samples from population-based databases. Core Resources in Administration, Genomics, Biostatistics and Bioinformatics, and Tissue Procurement and Analysis will enhance the specialized research of the SPORE. Career and Developmental Research Programs are also included.